Bottom Line:
Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects.This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux.It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

ABSTRACTAlzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ) in the etiology of Alzheimer's disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

Mentions:
We therefore acutely perfused oligomeric Aβ (0.1 µM, Fig. 1a) and analyzed its effects on evoked field potentials. After having established a stable baseline recording for 20 min, we perfused the slice cultures with oligomeric Aβ for 20 min. As seen in Figure 1 b and c, Aβ oligomers induced a significant synaptic depression within 10 min of exposure. We did not observe a difference in the fiber volley amplitude upon Aβ perfusion (Fig. 1 b and c), indicating that the acute Aβ-dependent synaptic depression does not act presynaptically. To further analyze the synaptic mechanisms of acute Aβ induced synaptic depression, we recorded evoked basal synaptic transmission in CA1 neurons in whole-cell patch clamp configuration (−60 mV holding potential) by stimulating the Schaffer collaterals. After 3 min of baseline recording, we perfused slices with oligomeric Aβ. As seen in Figure j, we observed a statistically significant synaptic depression within 10–15 minutes after Aβ application. This depression was specific for Aβ oligomers, since the scrambled form of Aβ (randomized Aβ amino acid sequence peptide), the monomeric Aβ as well as vehicle alone had no effect on basal synaptic transmission (Fig. 2a and 2b).

Mentions:
We therefore acutely perfused oligomeric Aβ (0.1 µM, Fig. 1a) and analyzed its effects on evoked field potentials. After having established a stable baseline recording for 20 min, we perfused the slice cultures with oligomeric Aβ for 20 min. As seen in Figure 1 b and c, Aβ oligomers induced a significant synaptic depression within 10 min of exposure. We did not observe a difference in the fiber volley amplitude upon Aβ perfusion (Fig. 1 b and c), indicating that the acute Aβ-dependent synaptic depression does not act presynaptically. To further analyze the synaptic mechanisms of acute Aβ induced synaptic depression, we recorded evoked basal synaptic transmission in CA1 neurons in whole-cell patch clamp configuration (−60 mV holding potential) by stimulating the Schaffer collaterals. After 3 min of baseline recording, we perfused slices with oligomeric Aβ. As seen in Figure j, we observed a statistically significant synaptic depression within 10–15 minutes after Aβ application. This depression was specific for Aβ oligomers, since the scrambled form of Aβ (randomized Aβ amino acid sequence peptide), the monomeric Aβ as well as vehicle alone had no effect on basal synaptic transmission (Fig. 2a and 2b).

Bottom Line:
Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects.This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux.It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.

ABSTRACTAlzheimer disease is characterized by a gradual decrease of synaptic function and, ultimately, by neuronal loss. There is considerable evidence supporting the involvement of oligomeric amyloid-beta (Aβ) in the etiology of Alzheimer's disease. Historically, AD research has mainly focused on the long-term changes caused by Aβ rather than analyzing its immediate effects. Here we show that acute perfusion of hippocampal slice cultures with oligomeric Aβ depresses synaptic transmission within 20 minutes. This depression is dependent on synaptic stimulation and the activation of NMDA-receptors, but not on NMDA-receptor mediated ion flux. It, therefore, appears that Aβ dependent synaptic depression is mediated through a use-dependent metabotropic-like mechanism of the NMDA-receptor, but does not involve NMDA-receptor mediated synaptic transmission, i.e. it is independent of calcium flux through the NMDA-receptor.